Detection of quantitative trait loci affecting serum cholesterol, LDL, HDL, and triglyceride in pigs

BMC Genetics

Karl Schellander¹  Christian Looft¹  Heinz Juengst¹  Ernst Tholen¹  Dawit Tesfaye¹  Mehmet Ulas Cinar¹  Do Ngoc Duy¹  Muhammad Jasim Uddin¹ 

[1] Institute of Animal Science, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany

关键词: F2 population;    serum lipids;    QTL;    pig;   

Others  :  1122689
DOI  :  10.1186/1471-2156-12-62

 received in 2011-02-07, accepted in 2011-07-13,  发布年份 2011

【 摘 要 】

Background

Serum lipids are associated with many serious cardiovascular diseases and obesity problems. Many quantitative trait loci (QTL) have been reported in the pig mostly for performance traits but very few for the serum lipid traits. In contrast, remarkable numbers of QTL are mapped for serum lipids in humans and mice. Therefore, the objective of this research was to investigate the chromosomal regions influencing the serum level of the total cholesterol (CT), triglyceride (TG), high density protein cholesterol (HDL) and low density protein cholesterol (LDL) in pigs. For this purpose, a total of 330 animals from a Duroc × Pietrain F2 resource population were phenotyped for serum lipids using ELISA and were genotyped by using 122 microsatellite markers covering all porcine autosomes for QTL study in QTL Express. Blood sampling was performed at approximately 175 days before slaughter of the pig.

Results

Most of the traits were correlated with each other and were influenced by average daily gain, slaughter date and age. A total of 18 QTL including three QTL with imprinting effect were identified on 11 different porcine autosomes. Most of the QTL reached to 5% chromosome-wide (CW) level significance including a QTL at 5% experiment-wide (GW) and a QTL at 1% GW level significance. Of these QTL four were identified for both the CT and LDL and two QTL were identified for both the TG and LDL. Moreover, three chromosomal regions were detected for the HDL/LDL ratio in this study. One QTL for HDL on SSC2 and two QTL for TG on SSC11 and 17 were detected with imprinting effect. The highly significant QTL (1% GW) was detected for LDL at 82 cM on SSC1, whereas significant QTL (5% GW) was identified for HDL/LDL on SSC1 at 87 cM. Chromosomal regions with pleiotropic effects were detected for correlated traits on SSC1, 7 and 12. Most of the QTL identified for serum lipid traits correspond with the previously reported QTL for similar traits in other mammals. Two novel QTL on SSC16 for HDL and HDL/LDL ratio and an imprinted QTL on SSS17 for TG were detected in the pig for the first time.

Conclusion

The newly identified QTL are potentially involved in lipid metabolism. The results of this work shed new light on the genetic background of serum lipid concentrations and these findings will be helpful to identify candidate genes in these QTL regions related to lipid metabolism and serum lipid concentrations in pigs.

【 授权许可】

   
2011 Uddin et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Burger K, Gimpl G, Fahrenholz F: Regulation of receptor function by cholesterol. Cell Mol Life Sci 2000, 57(11):1577-1592.
• [2]Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, Cowan LD, Gray RS, Welty TK, Go OT, et al.: LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler Thromb Vasc Biol 2000, 20(3):830-835.
• [3]Libby P: Inflammation in atherosclerosis. Nature 2002, 420(6917):868-874.
• [4]Austin MA: Plasma triglyceride and coronary heart disease. Arterioscler Thromb 1991, 11(1):2-14.
• [5]Yadav D, Pitchumoni CS: Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003, 36(1):54-62.
• [6]Rothschild MF, Cahpman AB: Factors influencing serum cholesterol levels in swine. J Hered 1976, 67(1):47-48.
• [7]Pond WG, Mersmann HJ, Young LD: Heritability of plasma cholesterol and triglyceride concentrations in swine. Proc Soc Exp Biol Med 1986, 182(2):221-224.
• [8]Harris KB, Pond WG, Mersmann HJ, Smith EO, Cross HR, Savell JW: Evaluation of fat sources on cholesterol and lipoproteins using pigs selected for high or low serum cholesterol. Meat Science 2004, 66(1):55-61.
• [9]Lu CD, Pond WG, Mersmann HJ, Su DR, Krook L, Harris JJ, Savell JW: Response to dietary fat and cholesterol in young adult boars genetically selected for high or low plasma cholesterol. J Anim Sci 1995, 73(7):2043-2049.
• [10]Gallardo D, Pena RN, Amills M, Varona L, Ramirez O, Reixach J, Diaz I, Tibau J, Soler J, Prat-Cuffi JM, et al.: Mapping of quantitative trait loci for cholesterol, LDL, HDL, and triglyceride serum concentrations in pigs. Physiol Genomics 2008, 35(3):199-209.
• [11]Chen R, Ren J, Li W, Huang X, Yan X, Yang B, Zhao Y, Guo Y, Mao H, Huang L: A genome-wide scan for quantitative trait loci affecting serum glucose and lipids in a White Duroc × Erhualian intercross F(2) population. Mamm Genome 2009, 20(6):386-392.
• [12]Hasler-Rapacz J, Ellegren H, Fridolfsson AK, Kirkpatrick B, Kirk S, Andersson L, Rapacz J: Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine. Am J Med Genet 1998, 76(5):379-386.
• [13]Aberg K, Sun G, Smelser D, Indugula SR, Tsai HJ, Steele MS, Tuitele J, Deka R, McGarvey ST, Weeks DE: Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa. Hum Biol 2008, 80(2):99-123.
• [14]Herrera VL, Didishvili T, Lopez LV, Myers RH, Ruiz-Opazo N: Genome-wide scan identifies novel QTLs for cholesterol and LDL levels in F2[Dahl RxS]-intercross rats. Circ Res 2004, 94(4):446-452.
• [15]Stylianou IM, Langley SR, Walsh K, Chen Y, Revenu C, Paigen B: Differences in DBA/1J and DBA/2J reveal lipid QTL genes. J Lipid Res 2008, 49(11):2402-2413.
• [16]Wang X, Paigen B: Genetics of variation in HDL cholesterol in humans and mice. Circ Res 2005, 96(1):27-42.
• [17]Miller ER, Ullrey DE: The pig as a model for human nutrition. Annu Rev Nutr 1987, 7:361-382.
• [18]Yang YG, Sykes M: Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol 2007, 7(7):519-531.
• [19]Ratcliffe HL, Luginbuhl H: The domestic pig: a model for experimental atherosclerosis. Atherosclerosis 1971, 13(1):133-136.
• [20]Casellas J, Noguera JL, Reixach J, Diaz I, Amills M, Quintanilla R: Bayes factor analyses of heritability for serum and muscle lipid traits in Duroc pigs. J Anim Sci 88(7):2246-2254.
• [21]Snieder H, van Doornen LJ, Boomsma DI: Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins: lessons from twin studies. Arterioscler Thromb Vasc Biol 1999, 19(12):2826-2834.
• [22]Misaki Kojima MSaMD: Gender-Related Differences in the Level of Serum Lipids in Meishan Pigs. J Health Sci 2008, 54:97-100.
• [23]Liu G, Jennen DG, Tholen E, Juengst H, Kleinwachter T, Holker M, Tesfaye D, Un G, Schreinemachers HJ, Murani E, et al.: A genome scan reveals QTL for growth, fatness, leanness and meat quality in a Duroc-Pietrain resource population. Anim Genet 2007, 38(3):241-252.
• [24]Liu G, Kim JJ, Jonas E, Wimmers K, Ponsuksili S, Murani E, Phatsara C, Tholen E, Juengst H, Tesfaye D, et al.: Combined line-cross and half-sib QTL analysis in Duroc-Pietrain population. Mamm Genome 2008, 19(6):429-438.
• [25]Edwards DB, Tempelman RJ, Bates RO: Evaluation of Duroc- vs. Pietrain-sired pigs for growth and composition. J Anim Sci 2006, 84(2):266-275.
• [26]de Koning DJ, Pong-Wong R, Varona L, Evans GJ, Giuffra E, Sanchez A, Plastow G, Noguera JL, Andersson L, Haley CS: Full pedigree quantitative trait locus analysis in commercial pigs using variance components. J Anim Sci 2003, 81(9):2155-2163.
• [27]Yasuda T, Ishida T, Rader DJ: Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis. Circ J 2010, 74(11):2263-2270.
• [28]Connelly PW, Hegele RA: Hepatic lipase deficiency. Crit Rev Clin Lab Sci 1998, 35(6):547-572.
• [29]Tahvanainen E, Syvanne M, Frick MH, Murtomaki-Repo S, Antikainen M, Kesaniemi YA, Kauma H, Pasternak A, Taskinen MR, Ehnholm C: Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. The LOCAT Study Invsestigators. J Clin Invest 1998, 101(5):956-960.
• [30]Jaye M, Lynch KJ, Krawiec J, Marchadier D, Maugeais C, Doan K, South V, Amin D, Perrone M, Rader DJ: A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet 1999, 21(4):424-428.
• [31]Rollins J, Chen Y, Paigen B, Wang X: In search of new targets for plasma high-density lipoprotein cholesterol levels: promise of human-mouse comparative genomics. Trends Cardiovasc Med 2006, 16(7):220-234.
• [32]de Koning DJ, Rattink AP, Harlizius B, van Arendonk JA, Brascamp EW, Groenen MA: Genome-wide scan for body composition in pigs reveals important role of imprinting. Proc Natl Acad Sci USA 2000, 97(14):7947-7950.
• [33]Thomsen H, Lee HK, Rothschild MF, Malek M, Dekkers JC: Characterization of quantitative trait loci for growth and meat quality in a cross between commercial breeds of swine. J Anim Sci 2004, 82(8):2213-2228.
• [34]Nezer C, Moreau L, Brouwers B, Coppieters W, Detilleux J, Hanset R, Karim L, Kvasz A, Leroy P, Georges M: An imprinted QTL with major effect on muscle mass and fat deposition maps to the IGF2 locus in pigs. Nat Genet 1999, 21(2):155-156.
• [35]Kadlecova M, Dobesova Z, Zicha J, Kunes J: Abnormal Igf2 gene in Prague hereditary hypertriglyceridemic rats: its relation to blood pressure and plasma lipids. Mol Cell Biochem 2008, 314(1-2):37-43.
• [36]Zaina S, Pettersson L, Ahren B, Branen L, Hassan AB, Lindholm M, Mattsson R, Thyberg J, Nilsson J: Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model. J Biol Chem 2002, 277(6):4505-4511.
• [37]Arya R, Duggirala R, Almasy L, Rainwater DL, Mahaney MC, Cole S, Dyer TD, Williams K, Leach RJ, Hixson JE, et al.: Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans. Nat Genet 2002, 30(1):102-105.
• [38]Fernandez ML, Webb D: The LDL to HDL cholesterol ratio as a valuable tool to evaluate coronary heart disease risk. J Am Coll Nutr 2008, 27(1):1-5.
• [39]Sing CF, Davignon J: Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 1985, 37(2):268-285.
• [40]Rohrer GA, Thallman RM, Shackelford S, Wheeler T, Koohmaraie M: A genome scan for loci affecting pork quality in a Duroc-Landrace F population. Anim Genet 2006, 37(1):17-27.
• [41]Uddin MJ, Cinar MU, Grosse-Brinkhaus C, Tesfaye D, Tholen E, Juengst H, Looft C, Wimmers K, Phatsara C, Schellander K: Mapping quantitative trait loci for innate immune response in the pig. Int J of Immunogenet 2011, 38:121-131.
• [42]Uddin MJ, Grosse-Brinkhaus C, Cinar MU, Jonas E, Tesfaye D, Tholen E, Juengst H, Looft C, Ponsuksili S, Wimmers K, et al.: Mapping of quantitative trait loci for mycoplasma and tetanus antibodies and interferon-gamma in a porcine F(2) Duroc × Pietrain resource population. Mamm Genome 2010, 21(7-8):409-418.
• [43]Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972, 18(6):499-502.
• [44]Grosse-Brinkhaus PC, Tholen E, Schellander K, J E: Feinkartierung von qtl für fleischqualitätsmerkmale auf dem porcinen chromosom 1. Züchtungskunde 2009, 81:63-68.
• [45]O'Connell JR, Weeks DE: PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998, 63(1):259-266.
• [46]Green PK, Falls a, Crooks S: Documentation for CRIMAP, Version 2.4. Washington University School of Medicine, St Louis, MO; 1990.
• [47]Knott SA, Marklund L, Haley CS, Andersson K, Davies W, Ellegren H, Fredholm M, Hansson I, Hoyheim B, Lundstrom K, et al.: Multiple marker mapping of quantitative trait loci in a cross between outbred wild boar and large white pigs. Genetics 1998, 149(2):1069-1080.
• [48]Seaton G, Haley CS, Knott SA, Kearsey M, Visscher PM: QTL Express: mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics 2002, 18(2):339-340.
• [49]Churchill GA, Doerge RW: Empirical threshold values for quantitative trait mapping. Genetics 1994, 138(3):963-971.
• [50]Visscher PM, Thompson R, Haley CS: Confidence intervals in QTL mapping by bootstrapping. Genetics 1996, 143(2):1013-1020.
• [51]Bosse Y, Chagnon YC, Despres JP, Rice T, Rao DC, Bouchard C, Perusse L, Vohl MC: Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study. J Lipid Res 2004, 45(3):419-426.
• [52]Guerra R, Wang J, Grundy SM, Cohen JC: A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1997, 94(9):4532-4537.
• [53]Hutter CM, Austin MA, Farin FM, Viernes HM, Edwards KL, Leonetti DL, McNeely MJ, Fujimoto WY: Association of endothelial lipase gene (LIPG) haplotypes with high-density lipoprotein cholesterol subfractions and apolipoprotein AI plasma levels in Japanese Americans. Atherosclerosis 2006, 185(1):78-86.
• [54]Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, et al.: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008, 40(2):189-197.
• [55]Ning Y, Xu L, Ren S, Pandak WM, Chen S, Yin L: StAR overexpression decreases serum and tissue lipids in apolipoprotein E-deficient mice. Lipids 2009, 44(6):511-519.
• [56]Feitosa MF, Province MA, Heiss G, Arnett DK, Myers RH, Pankow JS, Hopkins PN, Borecki IB: Evidence of QTL on 15q21 for high-density lipoprotein cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study (NHLBI FHS). Atherosclerosis 2007, 190(1):232-237.
• [57]Almasy L, Hixson JE, Rainwater DL, Cole S, Williams JT, Mahaney MC, VandeBerg JL, Stern MP, MacCluer JW, Blangero J: Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet 1999, 64(6):1686-1693.
• [58]Bosse Y, Chagnon YC, Despres JP, Rice T, Rao DC, Bouchard C, Perusse L, Vohl MC: Compendium of genome-wide scans of lipid-related phenotypes: adding a new genome-wide search of apolipoprotein levels. J Lipid Res 2004, 45(12):2174-2184.
• [59]Falchi M, Andrew T, Snieder H, Swaminathan R, Surdulescu GL, Spector TD: Identification of QTLs for serum lipid levels in a female sib-pair cohort: a novel application to improve the power of two-locus linkage analysis. Hum Mol Genet 2005, 14(20):2971-2979.
• [60]Soccio RE, Adams RM, Romanowski MJ, Sehayek E, Burley SK, Breslow JL: The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6. Proc Natl Acad Sci USA 2002, 99(10):6943-6948.
• [61]Lehman DM, Arya R, Blangero J, Almasy L, Puppala S, Dyer TD, Leach RJ, O'Connell P, Stern MP, Duggirala R: Bivariate linkage analysis of the insulin resistance syndrome phenotypes on chromosome 7q. Hum Biol 2005, 77(2):231-246.
• [62]Sonnenberg GE, Krakower GR, Martin LJ, Olivier M, Kwitek AE, Comuzzie AG, Blangero J, Kissebah AH: Genetic determinants of obesity-related lipid traits. J Lipid Res 2004, 45(4):610-615.
• [63]Elbein SC, Hasstedt SJ: Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q. Diabetes 2002, 51(2):528-535.
• [64]Coon H, Leppert MF, Eckfeldt JH, Oberman A, Myers RH, Peacock JM, Province MA, Hopkins PN, Heiss G: Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study. Arterioscler Thromb Vasc Biol 2001, 21(12):1969-1976.
• [65]Broeckel U, Hengstenberg C, Mayer B, Holmer S, Martin LJ, Comuzzie AG, Blangero J, Nurnberg P, Reis A, Riegger GA, et al.: A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 2002, 30(2):210-214.
• [66]Adeyemo AA, Johnson T, Acheampong J, Oli J, Okafor G, Amoah A, Owusu S, Agyenim-Boateng K, Eghan BA Jr, Abbiyesuku F, et al.: A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population. Atherosclerosis 2005, 181(2):389-397.
• [67]Couture P, Otvos JD, Cupples LA, Wilson PW, Schaefer EJ, Ordovas JM: Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J Lipid Res 1999, 40(10):1883-1889.
• [68]Kovar J, Suchanek P, Hubacek JA, Poledne R: The A-204C polymorphism in the cholesterol 7alpha-hydroxylase (CYP7A1) gene determines the cholesterolemia responsiveness to a high-fat diet. Physiol Res 2004, 53(5):565-568.
• [69]Wu T, Tian J, Cutler RG, Telljohann RS, Bernlohr DA, Mattson MP, Handa JT: Knockdown of FABP5 mRNA decreases cellular cholesterol levels and results in decreased apoB100 secretion and triglyceride accumulation in ARPE-19 cells. Lab Invest 2010, 90(6):963-965.
• [70]Reed DR, Nanthakumar E, North M, Bell C, Price RA: A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration. J Mol Med 2001, 79(5-6):262-269.
• [71]Saez ME, Gonzalez-Perez A, Martinez-Larrad MT, Gayan J, Real LM, Serrano-Rios M, Ruiz A: WWOX gene is associated with HDL cholesterol and triglyceride levels. BMC Med Genet 11:148.
• [72]Pollin TI, Hsueh WC, Steinle NI, Snitker S, Shuldiner AR, Mitchell BD: A genome-wide scan of serum lipid levels in the Old Order Amish. Atherosclerosis 2004, 173(1):89-96.
• [73]Feitosa MF, Rice T, North KE, Kraja A, Rankinen T, Leon AS, Skinner JS, Blangero J, Bouchard C, Rao DC: Pleiotropic QTL on chromosome 19q13 for triglycerides and adiposity: the HERITAGE Family Study. Atherosclerosis 2006, 185(2):426-432.
• [74]Lane RM, Farlow MR: Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res 2005, 46(5):949-968.
• [75]Feitosa MF, Rice T, Rankinen T, Province MA, Chagnon YC, Gagnon J, Leon AS, Skinner JS, Wilmore JH, Despres JP, et al.: Evidence of QTLs on chromosomes 13q and 14q for triglycerides before and after 20 weeks of exercise training: the HERITAGE Family Study. Atherosclerosis 2005, 182(2):349-360.
• [76]Klos KL, Kardia SL, Ferrell RE, Turner ST, Boerwinkle E, Sing CF: Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease. Arterioscler Thromb Vasc Biol 2001, 21(6):971-978.
• [77]Machleder D, Ivandic B, Welch C, Castellani L, Reue K, Lusis AJ: Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism. J Clin Invest 1997, 99(6):1406-1419.
• [78]Jacobs RL, Lingrell S, Zhao Y, Francis GA, Vance DE: Hepatic CTP:phosphocholine cytidylyltransferase-alpha is a critical predictor of plasma high density lipoprotein and very low density lipoprotein. J Biol Chem 2008, 283(4):2147-2155.
• [79]Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, et al.: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008, 40(2):161-169.
• [80]Colinayo VV, Qiao JH, Wang X, Krass KL, Schadt E, Lusis AJ, Drake TA: Genetic loci for diet-induced atherosclerotic lesions and plasma lipids in mice. Mamm Genome 2003, 14(7):464-471.
• [81]Peacock JM, Arnett DK, Atwood LD, Myers RH, Coon H, Rich SS, Province MA, Heiss G: Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: The NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol 2001, 21(11):1823-1828.
• [82]Yu Y, Wyszynski DF, Waterworth DM, Wilton SD, Barter PJ, Kesaniemi YA, Mahley RW, McPherson R, Waeber G, Bersot TP, et al.: Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia. J Lipid Res 2005, 46(10):2202-2213.